Bone loss and fragility from osteoporosis afflict more than 200 million people worldwide, including at least 10 million Americans. Current osteoporosis treatments are significantly deficient: most fail to reverse bone loss and/or have adverse effects that prohibit their long-term use. New therapeutic approaches are urgently needed. Recently the TGF- family ligand Activin A emerged as an important target in bone loss treatment. Activin A is highly expressed in bone and inhibits bone formation. More importantly, inhibition of Activin A greatly increases bone mass in animal models, demonstrating considerable potential as bone-forming therapy. However, off-target effects of current Activin A inhibitors make their therapeutic use impractical for this indication. To overcome this obstacle, an ideal Activin A inhibitor would retain its bone forming capabilities while minimizing off-target effects. We recently discovered a novel Activin A inhibitor, the extracellular protein `Cryptic'. We found that a `Cryptic' human Igg1-Ffucsion protein (Cryptic-Fc) binds Activin A with picomolar affinity and potently inhibits Activin A signaling. Strikingly, Cryptic-Fc showed greater target specificity than current Activin inhibitors, suggesting that Cryptic-Fc has the desired antagonistic properties. The goal of this phase I proposal is to demonstrate that Cryptic-derived polypeptides can promote bone formation in vivo with limited off-target effects. Successful proof of concept studies will pave th way for pre-clinical development of a Cryptic-derived polypeptide as therapeutic for osteoporosis.